Favorable Safety Profile in Novel TRK Inhibitor

Alexander Drilon, MD: Larotrectinib is probably one of the most tolerable tyrosine kinase inhibitors that we’ve explored in the clinic. If you look at the adverse event profile of the drug, you’ll note that most of the side effects were really grade 1 or 2, and when you look at the treatment-emergent adverse events—meaning any side effect that happened on the study, whether or not the doctor called it related to the drug or not—you’ll note that, at most, fatigue, nausea, constipation, for example, occurred in maybe 1 out of 4 patients or, at most, 1 out of 3 patients, and most of these were mild.

So this is not a situation like we’ve seen with sorafenib, sunitinib, or some of the other dirtier multikinase inhibitors that have been approved in the past for other indications. This drug can be very well tolerated, and that bodes well when you consider that these tumors can remain under control with this therapy for a very long period of time. So someone taking a pill every day, it really means something to them when the safety is unfavorable because it makes it amenable to chronic dosing.

There are unique side effects that we see with larotrectinib and other track inhibitors. Because the track pathway is highly involved in the development of the nervous system and the maintenance of the nervous system, there are patients [who] can experience occasional nervous stem–related side effects. So it may be 1 out 5 or 1 out of 4 patients [in whom] we can see some mild dizziness. And that mightn’t be more prominent when they go from a position of sitting or lying down or standing, for example. The dizziness can be amenable to things like meclizine, for example. In some patients where it might be mediated by a change in the blood pressure when they change positions, a pill like Midodrine might help with that side effect.

Interestingly, the TRK pathway also plays a role in weight gain—and we’re not used to seeing this side effect in many cancer therapies—but these track inhibitors can cause patients to gain weight over time because of a modulation in the appetite center in the brain. And so we watch out for this very carefully, obviously in cases that are relatively mild where it might be a 5-pound weight gain, for example. We advise patients to try to modify their diet if possible and increase exercise. Of course, these are things that are easier said than done. But in patients [who] might have more weight gain, we’ve, on occasion, had to refer them to endocrine, for example, and some of them have gotten pharmacologic agents to help deal with the appetite.

Beyond that, there are things, like mild paresthesia, also that can occur that are mediated by the effects of this drug on the nervous system. But the summary here is that while these side effects can occur in some patients, they’re not usually limiting of their daily activities. They tend to be mild overall. And the frequency is generally low compared to other side effects that we see.

Transcript Edited for Clarity

Transcript:

Alexander Drilon, MD: Larotrectinib is probably one of the most tolerable tyrosine kinase inhibitors that we’ve explored in the clinic. If you look at the adverse event profile of the drug, you’ll note that most of the side effects were really grade 1 or 2, and when you look at the treatment-emergent adverse events—meaning any side effect that happened on the study, whether or not the doctor called it related to the drug or not—you’ll note that, at most, fatigue, nausea, constipation, for example, occurred in maybe 1 out of 4 patients or, at most, 1 out of 3 patients, and most of these were mild.

So this is not a situation like we’ve seen with sorafenib, sunitinib, or some of the other dirtier multikinase inhibitors that have been approved in the past for other indications. This drug can be very well tolerated, and that bodes well when you consider that these tumors can remain under control with this therapy for a very long period of time. So someone taking a pill every day, it really means something to them when the safety is unfavorable because it makes it amenable to chronic dosing.

There are unique side effects that we see with larotrectinib and other track inhibitors. Because the track pathway is highly involved in the development of the nervous system and the maintenance of the nervous system, there are patients [who] can experience occasional nervous stem–related side effects. So it may be 1 out 5 or 1 out of 4 patients [in whom] we can see some mild dizziness. And that mightn’t be more prominent when they go from a position of sitting or lying down or standing, for example. The dizziness can be amenable to things like meclizine, for example. In some patients where it might be mediated by a change in the blood pressure when they change positions, a pill like Midodrine might help with that side effect.

Interestingly, the TRK pathway also plays a role in weight gain—and we’re not used to seeing this side effect in many cancer therapies—but these track inhibitors can cause patients to gain weight over time because of a modulation in the appetite center in the brain. And so we watch out for this very carefully, obviously in cases that are relatively mild where it might be a 5-pound weight gain, for example. We advise patients to try to modify their diet if possible and increase exercise. Of course, these are things that are easier said than done. But in patients [who] might have more weight gain, we’ve, on occasion, had to refer them to endocrine, for example, and some of them have gotten pharmacologic agents to help deal with the appetite.

Beyond that, there are things, like mild paresthesia, also that can occur that are mediated by the effects of this drug on the nervous system. But the summary here is that while these side effects can occur in some patients, they’re not usually limiting of their daily activities. They tend to be mild overall. And the frequency is generally low compared to other side effects that we see.